Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood, then new treatments and therapies can be designed to target these processes to prevent - and possibly cure - epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy, which produce widespread brain damage and cellular changes, thereby making the proximal cause of the disease difficult to ascertain. For the present proposal, we make a pivotal advance by utilizing a novel mouse model of epilepsy generated in the first term of this grant, in which epilepsy develops following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from a subset (>5%) of hippocampal dentate granule cells (DGC). Excessive activation of the mTOR pathway is implicated in the development of temporal lobe epilepsy, and the effect of this deletion - to induce the abnormal integration of newborn DGC - is important because abnormal newborn DGC are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our study provides direct evidence that abnormal DGC can cause epilepsy. Having demonstrating that abnormal DGC can be a proximal cause of epilepsy, we now seek to elucidate the mechanism(s) by which these cells promote seizures. Our guiding hypothesis is that abnormal DGCs promote epileptogenesis initially through cell-intrinsic increases in connectivity and activity, and secondarily by inducing changes among neighboring granule cells and their downstream targets. To test this hypothesis, we will determine the primary features of abnormal cells in SA1, the temporal associations between primary and secondary changes and epileptogenesis in SA2, and the functional significance of these changes in SA3 and 4.